Isatin chloride

It may be recalled that the first synthesis of indigo, by Baeyer, started from isatin chloride. (Formulate it.)... 

Isatin chloride and 3-hydroxyselenonaphthene are. mixed in benzene and the solution boiled, when the required compound separates as a violet precipitate. It dissolves sparingly in xylene with a red-violet fluorescence and deposition of violet-black needles, M.pt. 335° C. In concentrated or fuming sulphuric acid and chlorosulphonic acid it gives intense blue solutions, forming a water-soluble red-violet fluorescent sulphonic acid, which yields pale yellow alkali salts. 

Isatin Chloride.— Now isatin which is a di-ketone of di-hydro indole, or the tautomeric form, a mixed ketone and hydroxyl derivative of indole, yields a chloride when treated with phosphorus pentachloride. 

On treatment of isatin chloride with zinc dust and acetic acid the chlorine is eliminated and two hydrogens added with the formation of indigo. The reaction, with the formula for indigo which is supported, as we shall find, by other syntheses, is as follows ... 

Phosphorus pentachloride converts isatin to isatin chloride ... 

This compound is isomeric with indigotinj and is formed as a bye-product in the preparation of the latter from isatin chloride [22, 38]. 

Isatin is first submitted to tie action of phosphorus tri- or penta-chloride, and the resulting isatin chloride yields indigotin on reduction. In this case indigopurpurin is formed as a bye-product. 

When o-nitro-benzoylformic acid is reduced the amino compound formed loses water spontaneously and passes into isatin. Reduction of isatin chloride with zinc and acetic acid yields indigo. 

Adolf von Baeyer s first synthetic efforts on the preparation of indigo - for which the question of its correct structure remained unanswered - were not exploitable on an industrial scale due to the inaccessibility of the starting materials. Already in 1870, following his seven-stage isatin synthesis, Baeyer (Fig. 2.11) had succeeded in converting this material with phosphorus pentachloride into isatin chloride reductive dehalogenation of the latter with zinc yielded indigo directly. 

Meth-Cohn has developed an efficient one-pot synthesis of isatins 108 by the sequential treatment of iV-substituted formanilides 107 with oxalyl chloride, Hunig s base, and bromine... 

Spiro[3H-indole-3,5(4.H)-(l,2,4)triazoline]-2-one derivatives 204 have been obtained using microwave irradiation in the reaction between imines of isatin 203 and nitrile imines generated in situ from the corresponding hydrazonyl chlorides 199 (Scheme 9.63). The yields are in the range 85-95% and the reaction is complete within 5 min [110]. Similar reactions performed under thermal conditions were complete in 6-10 h and yields decreased to 20-30%. However, when the reaction was performed at ambient temperature, the products were obtained in excellent yields but only after a prolonged reaction time (30 h). 

The pharmacologically important tryptanthrine, a quinazoline alkaloid, is known for its antimycotic activity and is used against skin infections. This alkaloid is obtained from isatin (260) and o-azidobenzoyl chloride (261), as shown in Scheme 96. The adduct formed is cyclized via a Staudinger and an aza-Wittig reaction to afford tryptanthrine (262) (92H153). 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

The bisphenol 3,3-bis(4-hydroxyphenyl)- l-phenyl- l II-indol-2-one was prepared in a single step from /V-phenylisatin and molten phenol and not through the use of a phenolphthalein derivative. Although phenylisatin could have also been prepared through a modified isonitrosoacetanilide isatin process, it was formed in a one-pot process by reacting oxalic acid dichloride and aluminum chloride with diphenylamine. 

The synthesis of the right-hand fragment of ziprasidone started with a Wolff-Kishner reduction of isatin 43 to give the oxmdole 44 (Scheme 14). Friedel-Crafts acylation with chloroacetyl chloride afforded aryl ketone 45, which was reduced with triethylsilane in trifluoroacetic acid to the phenethyl chloride 46. The two fragments were joined by alkylation of 40 with 46 in the presence of Nal and Na2CO3 to give ziprasidone (4) in low yield. The yield of the coupling step was improved dramatically when the reaction was conducted in water (Scheme 15). 

Oxidation of isatin. Two products are possible from Baeyer-Villiger oxidation of isatin (1). Oxidation with K2S208 in sulfuric acid gives only the 1,4-beiuoxazine 2, whereas oxidation with H202-H0Ac gives the anhydride (3) of isatoic acid.1 An earlier preparation of compounds of type 2 involves reaction of o-aminophenols and oxalyl chloride.2... 

The decomposition of 2-nitrobenzoylacetone (72a) to isatin (74a) is considered to proceed via 2-acetylisatogen (73a).4 2-Acylisatogens were unknown until recently, when Robertson8 reported the preparation of 73b from the corresponding acetylene. 1-Hydroxyisatin (74b), formulated as the tautomeric 2-hydroxisatogen (73c) (Section II,A,l,a) is postulated as an intermediate in the decomposition of 2-nitrophenacyl chloride (72b)41 and 2-nitrobenzoyldiazomethane (72c).42... 

Isatin cr-chloride (2-chloroindolone, 160a) has been known for a long time.105 It is usually considered as a derivative of isatin,106 from which it is prepared by treatment with phosphorus pentachloride in boiling benzene. The methyl ether (160b) is readily prepared from the silver salt of isatin.107... 

The reaction of isatin cr-chloride (160a) with electron-rich aryl compounds, in the presence of a Lewis acid, gives indolone salts (161) from which the indolones (162) can be liberated on treatment with base.49, 108, 109 The reaction of 160a with various amines, under these conditions, has been reported108 to give the unstable indolones (163) although later attempts to repeat the synthesis were unsuccessful.49... 

Treatment of anilines with oxalyl chloride followed by cyclization of the intermediate 15 is a useful isatin synthesis. Generally a Lewis acid... 

Dihalogenation of oxindole followed by alkaline hydrolysis of the 3,3-dihalooxindole has been applied to the synthesis of some isa-tins.66,126,136 137b A number of oxindoles have been treated with nitrous acid to give isatin-3-oximes.100,138 Reduction of the oximes to 3-aminooxindoles followed by ferric chloride oxidation gave isatins.100,138 When this sequence was applied to 7-azaoxindole, the azaisatin 33 was... 

Stannous chloride reduction, in an acidic ethanol solution, of l-(o-nitrobenzoyl)isatin followed by treatment with base gave 71.153... 

Reduction of isatin-3-oximes to the corresponding 3-aminooxindole has been carried out using stannous chloride in acetic acid51 or in hydrochloric acid.92 3-Aminooxindole has also been obtained by electrochemical reduction288 and catalytic hydrogenation.169 Reduction... 

The synthesis of antiviral spiro-(3-lactam 51 begins with the benzylation of isatin 45 to give 1-benzylisatin 46, which affords Schiff s base 47 on reaction with anisidine in ethanol. The Schiff s base 47 on treatment with methoxyacetyl chloride by the chloride-imidate cycloaddition [85] route afforded a mixture of spiro E- and Z-azetidin-2-ones 48 and 49, which were separated by chromatography. The (Z)-N-arylazetidin-2-one 49 was further converted to desired 4-spiro-(3-lactam 51 by treatment with ceric ammonium nitrate and subsequently with tetrabutylammonium bromide in THF in the presence of pulverized KOH (Scheme 13). 

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

Synthetic indigo was made by A. von Baeyer in 1870 by treating isatin (5) with phosphorus trichloride and phosphorus in acetyl chloride [9], He obtained isatin by oxidizing indigo. The first complete synthesis of indigo (Scheme 1) was achieved in 1878, when von Baeyer succeeded in deriving isatin from phenylace-tic acid (6) [10],... 

The Menshutkin acid chloride was used by the author of [19] for the cyclization of isatin derivatives, and l-[(perhydro-2-alkoxy-l,3,6,2-dioxaazophosphocin-6-yl)methyl]isatins (53) were obtained ... 

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